The present invention relates to a process for the fixation or separation of ions, particularly of Pb, by per(3,6-anhydro)cylcodextrin derivatives.
Cyclodextrins or cyclomaltooligosaccharides are compounds having a natural origin formed by the linking of glucose units which are xcex1(1,4)-bonded.
Numerous works have revealed that these compounds could form inclusion complexes with hydrophobic molecules, thus permitting their solubilization in aqueous media. Numerous applications have been proposed for taking advantage of this phenomenon, particularly in the pharmaceutical field, as is described by D. Duchxc3xaane xe2x80x9cPharmaceutical application of cyclodextrinsxe2x80x9d in xe2x80x9cCyclodextrins and their industrial usesxe2x80x9d, D. Duchxc3xaane, Editions de Santxc3xa9, Paris, 1987, pp 213-257.
Pharmaceuticals have already been marketed in Japan, Italy and more recently in France, in the form of complexes in cyclodextrins. In France, the first active principle marketed in the form of an inclusion complex in a cyclodextrin is piroxicam, which is an anti-inflammatory agent marketed by Pierre Fabre Medicament under the name BREXIN(R). Among the very numerous modified derivatives of said cyclodextrins, those for which the cavity is turned on itself have interesting properties, even though their capacity to include organic molecules is lost or very limited. Compounds of this type are per(3,6-anhydro)cyclodextrins.
The synthesis of said peranhydrocyclodextrins has been described as from 1991 in document 1: Gadelle A. and Defaye J., Angew. Chem. Int. Ed. Engl., 1991, 30, 78-79; and document 2: Ashton P. R., Ellwood P., Staton I. and Stoddart J. F., Angew. Chem. Int. Ed. Engl., 1991, 30, 80-81) and it has been demonstrated that these derivatives have interesting solubilities both in water and organic solvents. Several subsequent studies (document 3: Yamamura H. and Fujita K. Chem. Pharm. Bull., 1991, 39, 2505-2508; document 4: Yamamura H., Ezuka T., Kawase Y., Kawai M., Butsugan Y. and Fujita K., J. Chem. Soc., Chem. Com., 1993, 636-637; and document 5: Yamamura H., Nagaoka H., Kawai M. and Butsugan Y., Tetrahedron Lett. 1995, 36, 1093-1094) have also demonstrated that these peranhydro derivatives could complex alkaline ions with a non-negligible selectivity.
Ashton et al in J. Org. Chem., 60, 1995, pp 3898-3903, have described the synthesis of the pernanhydro-xcex2-cyclodextrin derivative substituted in the 2-position by a methyl group.
However, this chemical modification has not been carried out with a view to optimizing the complexing or selectivity properties of the peranhydrocyclodextrins.
The present invention relates to the use for the separation or fixation of ions of derivatives of peranhydrocyclodextrins in which a chemical modification has been carried out for modifying their properties, particularly their selectivity with respect to the ions which they are liable to complex and in particular with respect to lead.
According to the invention, this modification relates to the hydroxyl groups present on said molecule, as well as the configuration of carbon C2, which can be reversed for leading to L-mannose-type derivatives.
Thus, the invention relates to a process for the fixation or separation ions, which consists of contacting a medium containing said ions with a derivative of per(3,6-anhydro)cyclodextrin, complying with one of the following formulas: 
in which at least one of the R1 represents the methoxy group and the other R1, which can be the same or different, represent a group complying with one of the formulas: OH, OR2, SH, SR2, OCOR2, NH2, NR2R3, CONR2R3, CONH2, CN, COOR2, COOH and R2, in which R2 represents a saturated or unsaturated, aliphatic or aromatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and R3 represents a hydrogen atom or a saturated or unsaturated, aromatic or aliphatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and n is equal to 6, 7 or 8, for fixing said ions in complex form with the per(3,6-anhydro)cyclodextrin derivative and for separating them from said medium.
In the cyclodextrin derivative of formula (I) or (II), the aliphatic or aromatic, hydrocarbon groups which can be used for R2 and R3 can be of various types. They are constituted by a carbon chain, in which certain carbon atoms can be replaced by one or more heteroatoms such as O, S and N and can have one or more ethylene or acetylene unsaturations. Moreover, the hydrocarbon group can have different substituents, in particular functional groups or halogen atoms. The aromatic hydrocarbon groups can be constituted by the optionally substituted tosyl group and phenyl group, e.g. by alkyl groups having 1 to 20 carbon atoms. R2 and R3 can in particular represent a straight or branched, alkyl group having 1 to 20 carbon atoms.
According to a preferred embodiment of the invention, intended more particularly for the separation of lead ions, the per(3,6-anhydro)cyclodextrin derivative is an xcex2-cyclodextrin derivative, i.e. in the aforementioned formulas (I) and (II), n is equal to 6.
Preferably, the derivative used complies with formula (I), in which all the R1 represent the methoxy group and n is equal to 6.
The ions which can be fixed or separated by the process according to the invention can be of various types. They can e.g. be ions of alkali metals, actinides, lanthanides or polluting metals such as lead, mercury, cobalt and strontium.
The process according to the invention more particularly applies to the separation and fixation of lead in complex form.
Thus, lead and its derivatives pollute the environment and are toxic both to man and animal. The main toxic effects affect the neurological development and the functioning of the nervous system. It is consequently necessary to separate and eliminate lead from the environment and store it safely.
In addition, products which would make it possible to ensure the lead decontamination of living beings by preventing the action of lead on the nervous system and on other organs, would be of great interest for solving these problems.
According to the invention, it has been found that derivatives of per(3,6-anhydro)cyclodextrins complying with the above formulas (I) and (II), have a high specificity for lead and are capable of complexing it with high yields able to reach 100%, even in the presence of other ions, such as sodium ions.
Thus, it is possible to separate the lead from the surrounding medium in complex form.
The invention also relates to complexes of lead and derivatives of per(3,6-anhydro)cyclodextrins of formulas (I) or (II) described hereinbefore.
For implementing the process according to the invention, it is possible to use the per(3,6-anhydro)cyclodextrin derivative of formula (I) or (II) in the form of an aqueous solution or organic solution.
When the medium containing the ions to be separated or fixed is an aqueous solution, it is possible to dissolve the cyclodextrin derivative in an organic solvent which is immiscible with the aqueous solution, e.g. in chloroform, in order to form the complex in the organic solution and separate it easily from the aqueous solution.
It is also possible to use the cyclodextrin derivative in aqueous solution, particularly for the lead decontamination of living beings.
Thus, it is known that cyclodextrin derivatives of formulas (I) or (II) are biocompatible compounds. They can consequently be administered to man or animals for ensuring the fixation of the lead in complex form and thus prevent its interaction with the organs of the human or animal body.
The invention also relates to a pharmaceutical composition for the lead decontamination of a living being, characterized in that it comprises a per(3,6-anhydro)cyclodextrin derivative complying with one of the following formulas: 
in which at least one of the R1 represents the methoxy group and the other R1, which can be the same or different, represent a group complying with one of the formulas: OH, OR2, SH, SR2, OCOR2, NH2, NR2R3, CONR2R3, CONH2, CN, COOR2, COOH and R2, in which R2 represents a saturated or unsaturated, aliphatic or aromatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and R3 represents a hydrogen atom or a saturated or unsaturated, aliphatic or aromatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and n is equal to 6, 7 or 8.
Preferably, the per(3,6-anhydro)cyclodextrin derivative used in this composition complies with formula (I), in which all the R1 represent the methoxy group and n is equal to 6.
This composition can be administered orally or by injection.
The aqueous solutions can incorporate up to 0.08 mole/l of the derivative of formula (I).
The administered quantities will depend on the lead contamination level and the weight of the patient.
The invention also relates to per(3,6-anhydro)cyclodextrin derivatives, usable in this process and which comply with one of the following formulas: 
in which at least one of the R1 represents the methoxy group and the other R1, which can be the same or different, represent a hydrogen atom or a group complying with one of the formulas: OH, OR2, SH, SR2, OCOR2, NH2, NR2R3, CONR2R3, CONH2, CN, COOR2, COOH and R2, in which R2 represents a saturated or unsaturated, aliphatic or aromatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and R3 represents a hydrogen atom or a saturated or unsaturated, aliphatic or aromatic, hydrocarbon group, which can have one or more heteroatoms chosen from among O, S and N, and n is equal to 6, 7 or 8, provided that all the R1 do not represent OCH3 when n=7 and that the derivative complies with formula (I).
The cyclodextrin derivatives used in the invention can be prepared by different processes.
When the cyclodextrin derivative complies with the above formula (I) or (II), in which at least one of the R1 represents the methoxy group, the other R1 representing OH or OCH3 and n is equal to 6, 7 or 8, they can be prepared by a process having the following stages:
1) reacting a peranhydrocyclodextrin complying with one of the formulas: 
xe2x80x83in which n is equal to 6, 7 or 8, with an alkali metal hydride for converting the OH group or groups into OM group or groups with M representing an alkali metal,
2) reacting the modified peranhydrocyclodextrin obtained in 1), with a methyl halide of formula CH3X, in which X represents a halogen atom and
3) if necessary, reacting the peranhydrocyclodextrin obtained in
2) with one or more reagents in order to substitute it by R1 groups differing from OCH3.
For performing stage 2), use is made of the quantity of CH3X necessary for modifying one or more of the OH groups of the cyclodextrin.
When the cyclodextrin derivative complies with the above formulas (I) or (II), in which the other R1 represent OR2, with R2 having the meaning given hereinbefore, except CH3, the above procedure is adopted for introducing the OCH3 group or groups, followed by reacting the derivative with a halide of formula R2X, in which R2 has the meaning given hereinbefore and X is a halogen atom.
When the cyclodextrin derivative complies with formula (I) or (II), in which the other R1 represent OCOR2, the above procedure is adopted for first introducing the methoxy groups and then the methyl derivative is reacted with an acid anhydride or halide of formulas R2COX or (R2CO)2O, in which R2 has the meaning given hereinbefore and X represents a halogen atom, in order to replace the remaining hydroxyls by OCOR2.
When it is wished to prepare a cyclodextrin derivative, in which the other R1 represent a halogen atom or a group of formula SH, SR2, NH2, NR2R3, CONR2R3, CONH2, CN, COOR2, COOH, or R2, with R2 and R3 having the meanings given hereinbefore, and n is equal to 6, 7 or 8, it is possible to carry out the following stages starting with a partly methylated peranhydrocyclodextrin, i.e. in which at least one of the R1 represents OCH3 and the other R1 represent OH and performing the following stages:
1) reacting said peranhydrocyclodextrin with an alkali metal hydride for converting the OH group or groups into OM group or groups with M representing an alkali metal,
2) reacting the modified peranhydrocyclodextrin obtained in 1) with a chloride of formula ClSO2R2 with R2 having the meaning given hereinbefore, for obtaining the derivative of formula (I) or (II), in which at least one of the R1 is a group of formula OSO2R2 and
3) reacting the derivative obtained in the second stage with one or more appropriate reagents for replacing OSO2R2 by the desired R1 group.
In this process, the per(3,6-anhydro)cyclodextrin is firstly transformed into alkoxide by the action of alkali metal hydride and said alkoxide is then converted into a derivative having a starting group of formula OSO2R2, which is then reacted in one or more stages with one or more appropriate reagents for replacing said starting group by the desired R1 group.
Thus, in the case where R1 has to represent NH2, it is possible to react N3M and the compound defined in 2). The thus obtained compound, called an azide, can undergo a catalytic hydrogenation or can be treated in the presence of ammonia NH3, in order to obtain the product where R1 is to represent NH2.
The product where R1 is to represent NR2R3 is obtained by reacting the compound defined in 2) with the compound NHR2R3.
In the case where R1 is to represent SH or SR2, it is possible to react the compound defined in 2) with a halide Xxe2x88x92, which gives the compound with (R1xe2x80x94X), which is then reacted with HSxe2x88x92 or R2Sxe2x88x92 to give a compound, where R1 is to represent SH or SR2.
When R1 is to represent a hydrocarbon group, reaction takes place with R21LiCu (R1 representing a hydrocarbon group) to give a final compound, where R1 then represents a hydrocarbon group.
In the same way, the compound where R1 represents a halogen can react with CNxe2x88x92 to give a final compound, where R1 will represent CN.
In addition, the compound where R1 represents CN can, by controlled hydrolysis, give a compound where R1 will represent CONH2. The compound where R1 represents CN can, by complete hydrolysis, give a compound where R1 will represent COOH.
The compound where R1 represents COOH can, by esterification, give a compound where R1 will represent COOR2.
The compound where R1 represents COOH can react on NHR2R3 in the presence of DCC (dicyclohexylcarbodiimide) to give a compound where R1 will represent NR2R3.
The cyclodextrin derivatives according to the invention have numerous advantages. In particular, when they are persubsituted, i.e. when all the R1 are different from the OH group, the derivatives have a good solubility in organic solvents, such as chloroform, acetone, tetrahydrofuran, etc. This solubility is of interest for their use in ionic separation, because it makes it possible to carry out the separation by liquid-liquid exchange processes, which are well known in the art.
Moreover, the possibility of introducing one or more particular chemical groups makes it possible to make to measure complexing agents for very varied ions. This is increased by the fact that the three natural cyclodextrins usable as a starting material, have different cavity diameters, which can lead to a supplementary selection relative to the size of the ions to be separated.
The starting products of formulas (III) or (IV) used in the invention can be prepared by conventional processes, such as those described in the aforementioned documents 1 and 2 of Gadelle A. et al. and Ashthon P. R. et al.
Other features and advantages of the invention can be better gathered from studying the following examples, given in an illustrative and non-limitative manner with reference to the attached drawing.